scholarly journals Peripheral Neuropathy (PN) with Immunomodulatory Drugs in Patients with Multiple Myeloma (MM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5677-5677
Author(s):  
Melinda Mezo ◽  
Carmen Castaneda ◽  
Lilia Weiss ◽  
Neil Minton ◽  
Damien Hirsch ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Peripheral Neuropathy ◽  
Dose Reduction ◽  
Randomized Clinical Trials ◽  
Employment Equity ◽  
Therapy Discontinuation ◽  
Drug Induced ◽  
Narrow Scope ◽  
Therapeutic Class ◽  
Equity Ownership

Abstract Background: PN is a recognized adverse event (AE) with thalidomide (THAL). Despite similarities between THAL and its analogues (lenalidomide [LEN] and pomalidomide [POM]) that include structural, binding target, and common drug-induced substrates, the result of unshared downstream molecular, cellular, and microenvironment effects among the compounds is a diverse array of biological responses and different efficacy and safety outcomes (Bjorklund CC, et al. Blood Cancer J. 2015;5:e354). This underscores the mechanistic diversity of a family of agents rather than the mechanistic uniformity of a therapeutic class. In untreated patients with MM, low incidence (3%-13%) of symptomatic PN has been reported, while the estimated rate was much higher (40%-60%) for subclinical PN (Kwan JY. Neurol Clin. 2007;25:47-69). Objective: To describe the frequency, severity, and tolerability of PN in patients with MM treated with THAL-, LEN-, and POM-based therapy from Celgene-sponsored pivotal and other registrational studies. Methods: AEs of new and worsening PN were analyzed for THAL-, LEN-, and POM-based therapy in 9 randomized clinical trials in 3518 patients with MM. Eight of the 9 clinical trials included patients with baseline grade 1 PN, while 1 clinical trial excluded all patients with PN. The search for PN used narrow-scope Standardised MedDRA Query "peripheral neuropathy." The AEs were rated per NCI-CTCAE. Results: PN was reported more frequently in patients in the THAL-based pool (36.2%; 460/1272) compared with the LEN-based pool (23.2%; 400/1727) and POM-based pool (12.3%; 64/519). Generally, PN was grade 1/2: 27.2% in the THAL-, 19.9% in the LEN-, and 11.4% in the POM-based pool. The frequency of patients with grade 3/4 PN events was 9.0% in the THAL-, 3.2% in the LEN-, and 1.0% in the POM-based pool. The frequencies of patients with serious AEs (SAEs) of PN were low (≤ 1%) for both THAL- and LEN-based pools; no patient had an SAE of PN in the POM-based pool. PN led to THAL-based therapy discontinuation in 7.0% and dose adjustments (reduction, modification, or interruption) in 16.7% of the patients. PN led to LEN-based therapy discontinuation in 0.6%, dose reduction in 2.5%, and interruption in 1.5% of the patients. PN led to POM-based therapy discontinuation in 0.4%, dose reduction in 0.6%, and interruption/reduction in 0.2% of the patients. Conclusions: The frequency and severity of PN and therapy discontinuation or modification is highest in THAL-treated patients with MM compared with LEN- and POM-treated patients. LEN and POM demonstrate improved safety for PN compared with THAL. Disclosures Mezo: Celgene: Employment, Equity Ownership. Castaneda:Celgene: Employment. Weiss:Celgene: Consultancy, Employment, Equity Ownership. Minton:Celgene: Employment, Equity Ownership. Hirsch:Celgene: Employment, Equity Ownership. Renz:Celgene: Employment. Arunagiri:Celgene: Employment. Brown:Celgene: Employment, Equity Ownership. Gambini:Celgene: Employment, Equity Ownership. Peng:Celgene: Employment. Yu:Celgene: Employment, Equity Ownership. Yu:Celgene: Employment. Freeman:Celgene: Employment.

Evaluation of Relative Dose Intensity (RDI) by Age in Patients (pts) with Non-Hodgkin Lymphoma (NHL) Receiving Pegfilgrastim and CHOP Based Chemotherapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4880-4880
Author(s):  
Lodovico Balducci ◽  
May Mo ◽  
Steve Abella ◽  
Alan Saven
Keyword(s):  
Clinical Trials ◽  
Retrospective Analysis ◽  
Dose Reduction ◽  
Multiple Regression ◽  
Dose Intensity ◽  
B Cell Lymphoma ◽  
Primary Prophylaxis ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Delay

Abstract Abstract 4880 Introduction: The standard of care for aggressive NHL is treatment (tx) with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with rituximab (R). Improved outcomes are associated with retention of dose and schedule. Pegfilgrastim prophylaxis reduces the severity and duration of neutropenia, contributing to fewer dose delays and reductions and higher RDI. A retrospective analysis of pegfilgrastim NHL clinical trials showed that pegfilgrastim primary prophylaxis maintained RDI for CHOP/CHOP-R; a greater number of younger than older pts had > 85% RDI (Mo et al. Pan Pacific Lymphoma Conference 2011; poster). Here we further examine the association of age with RDI for CHOP/CHOP-R in NHL pts receiving pegfilgrastim. Methods: This retrospective analysis pooled data from 5 pegfilgrastim NHL clinical trials (1 single-arm and 4 randomized controlled studies). Pts received up to 6 cycles of CHOP/CHOP-R every 2 (Q2W) or 3 (Q3W) weeks. Data from the pegfilgrastim primary prophylaxis tx arms were combined. RDI and the incidence of dose delay, reduction, discontinuation, and adverse events (AE) leading to dose alteration/discontinuation were analyzed in the CHOP/CHOP-R regimens combined and stratified by age group (< 65, 65–75, and > 75 years [yr] ) and schedule (Q2W and Q3W). RDI during tx exposure and RDI adjusted by the planned 6 cycles of tx were calculated. Overall RDI of the regimen was calculated as the average of RDI of cyclophosphamide and doxorubicin. Dose delay: > 3 days of delay for any cycle after cycle 1. Dose reduction: ≥ 20% reduction from the planned dose of cyclophosphamide or doxorubicin for any cycle. Dose discontinuation: not completing all planned 6 cycles of tx for reasons other than death/disease progression. RDI was also evaluated with a multiple regression model using tx group, age, stage, sex, race and comorbidity as explanatory variables. Results: In the Q3W regimen (N = 137), 50% of pts were women, 36% had stage IV disease, and 23% were > 75 yr. In studies with available histology data, most pts had diffuse large B cell lymphoma. The incidence of pts with > 85% RDI during tx exposure: 89%, 86% and 81% for pts < 65, 65–75 and > 75 yr, respectively. The incidence of pts with > 85% adjusted RDI: 74%, 55% and 47%, respectively. The incidence of pts who completed all 6 cycles of tx: 78%, 56% and 47%, respectively. The incidence of dose reduction: 7%, 21% and 13%, respectively. The incidence of dose discontinuation: 19%, 36% and 47%, respectively. The incidence of dose delay was similar among age groups. Multiple regression analysis showed age and cancer stage as potential factors associated with RDI (p = 0.0290 and 0.0145, respectively). The table shows AEs leading to dose alteration/discontinuation. Q2W data will be presented separately. Conclusions: In this pooled population the incidence of pts with > 85% RDI adjusted by the planned 6 cycles of tx was lower in older pts as fewer older pts completed all 6 cycles of tx. Pts < 65 yr had a lower incidence of AE leading to dose alteration/discontinuation. The AE profile was widely spread across hematological and non-hematological toxicities. Unlike prior reports where myelosuppression frequently caused reduced RDI, myelotoxicity was an infrequent cause of therapy alteration/discontinuation with pegfilgrastim primary prophylaxis (< 7%). Pegfilgrastim use in elderly pts maintained RDI during tx exposure. Further research is needed to address non-hematologic causes of tx interruptions in elderly pts receiving CHOP based chemotherapy. Disclosures: Balducci: Jennsen: Honoraria; Novartis: Honoraria; Cephalon: Honoraria; Amgen Inc.: Honoraria. Mo:Amgen Inc.: Employment, Equity Ownership. Abella:Amgen Inc.: Employment, Equity Ownership.

scholarly journals Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4739-4739
Author(s):  
Pieter Sonneveld ◽  
Maria-Victoria Mateos ◽  
Adrián Alegre ◽  
Thierry Facon ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Indirect Comparison ◽  
Employment Equity ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

scholarly journals Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3543-3543 ◽  
Author(s):  
Alexis A. Thompson ◽  
Mark C. Walters ◽  
Janet L. Kwiatkowski ◽  
Suradej Hongeng ◽  
John B. Porter ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Adult Patients ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were &lt;12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of &gt;11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of &gt;11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

Relationship Between Lenalidomide Dose Modification and Duration Of Treatment In Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2944-2944
Author(s):  
Kathy Lang ◽  
Gary Binder ◽  
Iris Lin ◽  
Dejan Milentijevic ◽  
Huan Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Reduction ◽  
Research Funding ◽  
Duration Of Treatment ◽  
Employment Equity ◽  
Medical Claims ◽  
Dose Modification ◽  
Equity Ownership ◽  
Dose Change ◽  
Dose Reductions

Abstract Introduction A number of studies have shown clinical benefits for multiple myeloma (MM) patients who continue to stay on therapy with lenalidomide (LEN), including progression-free survival (PFS) and overall survival (OS) (Palumbo A, et al. NEJM. 2013, McCarthy P, et al. NEJM. 2013, Boccadoro. JCO. 2013). Dose modification is one factor used by physicians to achieve sustained duration of treatment (DOT), particularly to manage toxicities and/or pursue a continuous therapy regimen; in a clinical trial of LEN in newly diagnosed MM (NDMM) patients (pts) followed-up for a median of 30 mos, 42% of pts experienced a dose reduction (Palumbo A, et al. NEJM. 2012). This analysis evaluated whether there is supporting evidence, in a real-world setting, for physicians using LEN dose modification to achieve a longer time on therapy. Objective Medical claims analysis was performed to evaluate the relationship between lenalidomide (LEN), dose modification and DOT among patients with NDMM. Methods A retrospective cohort analysis was conducted using a claims database from a large US payer, covering approximately 14 million commercially insured and Medicare advantage members. Patients with at least two outpatient or one inpatient medical claims associated with a diagnosis of MM (ICD-9-CM code: 203.0x) between Jan 1, 2008 and Oct 31, 2012 were extracted from the database. Index date was defined as the date of the first diagnosis of MM. A minimum of 12 months pre-index and 6 months post-index enrollment with no MM treatment was required to define the NDMM patient population. To avoid DOT limitations imposed by fixed-length induction therapy, only pts without claims for stem cell transplant (SCT) were evaluated. DOT was compared among the group treated with LEN who had dose modification (increase or decrease in number of mg per day) relative to the group with no dose modification. Results Among the 236 pts meeting the inclusion criteria, 69 (29%) pts had LEN dose reductions, 15 (6%) had dose increases, and 152 (64%) had no dose change. DOT in pts without a dose change was 7.33 months ± 7.62 (mean ± SD), while pts who had a dose reduction had significantly longer DOT of 14.63 months ± 10.47 (p<0.01). Of the 69 pts with dose reductions, DOT before dose reduction was 5.18 months ± 4.82 compared with 9.46 months ± 10.26 after dose reduction (p<0.01, paired). The subset of pts who were still on LEN therapy at the end of the data window (N=27) showed a similar association between dose reduction and DOT, with DOT of 20.29 months ± 11.62 and 11.99 months ± 9.29 in dose reduction and non-dose reduction subgroups (p<0.01), respectively. Conclusion NDMM pts who had dose reductions of LEN had twice the duration of therapy compared with pts without dose reductions. This analysis suggests that dose modification of MM treatment may be an effective tool to help pts achieve the benefits associated with longer time on therapy. Future clinical studies are needed to determine the best approaches to dose adjustment to improve disease control. Disclosures: Lang: Celgene: Research Funding. Off Label Use: Lenalidomide is a thalidomide analog indicated for the treatment of multiple myeloma, in combination with dexamethasone, in patients who have received at least one prior therapy. Binder:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding. Milentijevic:Celgene: Consultancy. Huang:Celgene: Research Funding. Nagarwala:Celgene: Employment, Equity Ownership. Harwin:Celgene: Honoraria.

Real-World Analysis Of Celgene Global Drug Safety (GDS) Database: Early Permanent Discontinuation (D/C) Of Lenalidomide (LEN) In Patients (Pts) With Myelodysplastic Syndromes (MDS) Due To Nonserious (NS) Rash

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2975-2975 ◽  
Author(s):  
Lilia Weiss ◽  
Dianna Gary ◽  
Arlene S. Swern ◽  
John Freeman ◽  
Mary M. Sugrue
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Clinical Trial Data ◽  
Red Blood Cell Transfusion ◽  
Stevens Johnson Syndrome ◽  
Topical Steroids ◽  
Employment Equity ◽  
Dose Modification ◽  
Equity Ownership ◽  
Dose Modifications

Abstract Background LEN (Revlimid(r)) is approved for the treatment (Tx) of transfusion-dependent anemia due to IPSS low- or intermediate-1-risk MDS associated with del(5q), with or without additional cytogenetic abnormalities (US), or with isolated del(5q) only (EU). In LEN MDS clinical trials, myelosuppression leading to neutropenia or thrombocytopenia was the leading cause of dose modifications and permanent D/C (Fenaux et al. 2011; List et al. 2006). Onset of red blood cell transfusion independence (> 56 days) occurred at a median of 4.6 weeks to LEN 10 mg (days 1-21) in MDS-004, and at a median of 4.3 weeks in MDS-003. Given 90% of pts who achieved a transfusion benefit did so by completion of 3 cycles of LEN (LEN PI, 2013), it is important to optimally manage early toxicities associated with LEN Tx to achieve best outcomes. Using the Celgene GDS database, adverse events (AEs) associated with dose modifications and early permanent D/C of LEN in MDS pts were analyzed. Methods The Celgene GDS database was searched for AEs spontaneously reported between Dec 27, 2005 and Jun 13, 2013 by health care practitioners and MDS pts who received LEN. A pt may be represented in the database by > 1 report. AE information could include indication, time to onset, severity and outcome of AE, and action taken with LEN. AE severity was defined as NS or serious (S; requiring hospitalization or intervention, disabling, important medical event, life threatening, or fatal). Actions taken with LEN included permanent D/C, dose modification (dose reduction or interruption) or no dose change. Incomplete AE reports were excluded from the analysis. Results Of 42,132 pts with MDS exposed to LEN in the global post-marketing setting, 16,942 reports representing 36,793 AEs were submitted to the Celgene GDS database. The action taken with LEN was reported for the majority (73%) of AEs. The 5 most common AEs reported were neutropenia (n = 1839; 5.0%), thrombocytopenia (n = 1754; 4.8%), infections (n = 1617; 4.4%), rash (n = 1593; 4.3%), and anemia (n = 1410; 3.8%), consistent with the known safety profile of LEN (Figure). Neutropenia and thrombocytopenia were the most common AEs leading to dose modification, while, unexpectedly, rash was the most common AE leading to permanent LEN D/C. Most (91%) rash was reported as NS. Of NS rash, 26% reported permanent D/C. For all rash events, 29% (5% S vs 24% NS) reported permanent D/C, while dose modification was reported in 37% (3% S vs 34% NS) and no change in dose was reported in 34% (1% S vs 33% NS). Median time to rash onset was 9 days (range, 1-1460) for events leading to permanent D/C vs 30 days (range, 1-1825) for events leading to dose modification or no change in dose. Of the 24% permanent D/C of LEN due to NS rash, 72% permanently D/C within the first 2 cycles. Of the NS rash AEs reporting dose modifications, 76% reported an AE outcome of recovered/recovering. Conclusions Consistent with published clinical trial data, this analysis of the Celgene GDS database showed that neutropenia and thrombocytopenia were the most commonly reported AEs leading to dose modification of LEN in MDS. Unexpectedly, NS rash led to the highest rate of early permanent LEN D/C, suggesting differences in rash management in the real world vs clinical trials. The LEN label recommends permanent D/C of LEN for serious AEs (angioedema, grade [Gr] 4 rash, exfoliative or bullous rash, or if Stevens-Johnson-Syndrome or toxic epidermal necrolysis is suspected); for Gr 2-3 skin rash, dose interruption or D/C should be considered (LEN PI, 2013; SmPC, 2013). Recently, all-Gr rash was shown to be significantly associated with LEN Tx of pts with a variety of malignancies (Nardone et al. 2013). LEN-related rash in MDS has been reported in the literature to be generally self-limiting, resolving within 2-3 weeks of Tx, with NS rash being managed using antihistamines, topical steroids, or a short course of corticosteroids until rash is Gr 1 or resolved; dose interruptions for 7-14 days were suggested for Gr 3 or intolerable Gr 2 rash. LEN can generally be restarted thereafter without recurrence of rash (Giagounidis et al. 2008; Nardone et al. 2013). This analysis of Celgene GDS database showed unexpectedly that NS rash was the most common reason for early permanent D/C. NS rash should be managed by following clinical guidance with dose modification/interruption as appropriate to achieve optimal pt outcomes. Disclosures: Weiss: Celgene Corporation: Employment, Equity Ownership. Gary:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene: Employment, Equity Ownership. Freeman:Celgene Corporation: Employment. Sugrue:Celgene: Employment, Equity Ownership.

scholarly journals Assessment of Romiplostim Immunogenicity in Adult Patients in Clinical Trials and in a Global Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2427-2427 ◽  
Author(s):  
Troy E. Barger ◽  
Andy Boshier ◽  
Vibha Jawa ◽  
June Kim ◽  
Daniel T. Mytych ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Platelet Count ◽  
Research Funding ◽  
Phase 1 ◽  
Adult Patients ◽  
Employment Equity ◽  
Lower Baseline ◽  
Increased Risk ◽  
Equity Ownership ◽  
Global Registry

Abstract Background: Romiplostim (Nplate®) is a thrombopoietin (TPO) receptor agonist approved for the treatment of adult chronic immune thrombocytopenia (ITP). The formation of antibodies (Abs) against romiplostim may lead to a loss of response, and a theoretical risk exists that an immune response against romiplostim might lead to the formation of Abs that bind both romiplostim and native TPO. We therefore examined Abs against romiplostim and TPO in adult patients (pts) enrolled in clinical trials and in a global postmarketing registry based on spontaneously submitted requests for Ab testing. Methods: The clinical trial population included adult pts (age ≥18 years at screening) with ITP who received ≥1 dose of romiplostim in any of 13 completed romiplostim clinical trials, including phase 1 (n=1), phase 2 (n=3), phase 1/2 (n=1), phase 3 (n=5), and open-label extension (n=3) studies. Duration of romiplostim treatment varied among the trials. The postmarketing global registry population included romiplostim-treated adult pts with ITP who had blood samples sent for Ab testing. Serum samples from the clinical trials and the registry were assessed for romiplostim and TPO binding Abs in a surface plasmon resonance (SPR)-based immunoassay, and samples positive for binding were assessed for neutralizing activity in a cell-based bioassay, as previously described (Jawa et al. Ann Hematol 2010). Pt characteristics were summarized for those who did and did not develop Abs in the clinical trials. Pts in the registry found to have romiplostim neutralizing Abs were to be followed every 3 months for up to 12 months. No formal statistical analyses were conducted. Results: A total of 1046 romiplostim-treated pts from clinical trials were available for analysis. At baseline, 958 pts had romiplostim Ab results: 35 pts (3.7%) were positive for binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 961 pts had romiplostim Ab results: 80 pts (8.3%) were positive for binding Abs and 4 pts (0.4%) were positive for neutralizing Abs, independent of the baseline result. Sixty (6.2%) pts negative for anti-drug Abs at baseline developed romiplostim binding Abs during the clinical trials. Characteristics of the pts who did and did not develop romiplostim binding Abs are presented in Table 1. Development of romiplostim binding Abs was more frequent in pts with ITP duration >3 years at baseline (70.0% vs 57.4%), prior splenectomy (48.3% vs 37.5%), and a history of allergies (21.7% vs 8.4%). Pts who developed Abs also had lower baseline TPO levels (84.8 pg/mL vs 104.6 pg/mL), lower baseline platelet counts (12.5× 109/L vs 20.5 × 109/L), and a higher number of previous ITP treatments (median 3 vs 2). Four of the 60 pts with romiplostim binding Abs developed romiplostim neutralizing Abs after treatment (0.38% of 1046 pts overall; Table 2). The emergence of neutralizing Abs did not appear to be related to romiplostim dose or platelet count. The neutralizing Abs were directed against the peptide component of romiplostim and did not bind native TPO. Pts in the clinical trials were also tested for TPO Abs. At baseline, 956 pts had TPO Ab results: 31 pts (3.2%) were positive for TPO binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 960 pts had TPO Ab results: 33 pts (3.4%) were positive for TPO binding Abs and no pts were positive for neutralizing Abs. Of the 184 adult pts in the registry, 9 (4.9%) were positive for binding Abs: 5 were positive for romiplostim binding, 2 for TPO binding, and 2 for romiplostim and TPO binding. No predose Ab results were available for these pts. One pt received romiplostim for 11 months at a dose of 2 µg/kg and then experienced an abrupt fall in platelet count even as romiplostim dose was increased to 10 µg/kg. The pt tested positive for romiplostim binding and neutralizing Abs. Romiplostim was discontinued, and the pt was switched to alternative therapy. Conclusions: An analysis of pts in 13 clinical trials shows that pts with indicators of more severe disease (longer duration of ITP, prior splenectomy, and a higher number of previous ITP treatments) may be at increased risk of developing romiplostim binding Abs. Development of romiplostim neutralizing Abs was uncommon in the clinical trials, and these Abs did not bind native TPO. Data from a postmarketing registry showed that the overall risk of clinically significant immunogenicity following exposure to romiplostim is low. Disclosures Barger: Amgen Inc.: Employment, Equity Ownership. Boshier:Sanofi: Other: rents a room to a Sanofi employee; Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Mytych:Amgen Inc.: Employment, Equity Ownership. Park:Amgen Inc.: Employment, Equity Ownership. Kuter:Amgen Inc.: Consultancy; Argenx: Consultancy; Rigel: Consultancy, Research Funding; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Principia: Research Funding; Protalex: Research Funding; Pfizer: Consultancy; Bioverativ: Consultancy, Research Funding; ONO: Consultancy; Syntimmune: Consultancy; BMS: Research Funding.

scholarly journals AG-221, a Small Molecule Mutant IDH2 Inhibitor, Remodels the Epigenetic State of IDH2-Mutant Cells and Induces Alterations in Self-Renewal/Differentiation in IDH2-Mutant AML Model in Vivo

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 437-437 ◽  
Author(s):  
Alan H. Shih ◽  
Kaitlyn R Shank ◽  
Cem Meydan ◽  
Andrew M. Intlekofer ◽  
Patrick Ward ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Clinical Trials ◽  
Small Molecule ◽  
Leukemia Cells ◽  
Employment Equity ◽  
Advisory Committees ◽  
Self Renewal ◽  
Equity Ownership ◽  
The Impact

Abstract Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are observed in patients with acute myeloid leukemia (AML). Leukemia-associated IDH1/2 mutations result in aberrant accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). The observation that IDH1/2 mutations are mutually exclusive with TET2 mutations led to the finding that IDH1/2-mutant production of 2-HG inhibits TET2 function and induces changes in DNA methylation. These data suggested that small molecule inhibition of mutant IDH enzymes might reverse the aberrant epigenetic remodeling of IDH-mutant leukemia cells and restore normal hematopoietic differentiation. We therefore investigated the in vivo efficacy of AG-221, a potent and selective mutant IDH2 inhibitor in early-phase clinical trials, in murine models of IDH2-mutant leukemia. We first assessed the impact of AG-221 on 2-HG production in hematopoietic cells expressing mutant IDH2-R140Q. AG-221 treatment (10mg/kg or 100mg/kg bid) led to a reduction in 2-HG in vivo (96.7% below pre-treatment levels). Moreover, AG-221 treatment restored megakaryocyte-erythroid progenitor (MEP) differentiation that is suppressed by mutant IDH2 expression in vivo (mean MEP% mean, 39% Veh vs 50% AG-221). We next investigated the impact of mutant IDH2 inhibition with AG-221 on DNA methylation in vivo. We used eRRBS, a bisulfite-based next-generation sequencing platform, to assess the effect of AG-221 therapy on DNA methylation. AG-221 or vehicle therapy treated LSK stem cells (lin- Sca+ c-Kit+) were sorted from mice expressing IDH2-R140Q and evaluated by eRRBS. AG-221 therapy reversed the effects of mutant IDH2; we observed a significant reduction in DNA methylation, including 180 genes that had 20 or more hypomethylated differentially methylated cytosines (DMCs) following treatment. 84 of these genes had reduced methylation at 10 or more DMCs in the gene promoter with AG-221 therapy compared to vehicle. Mutant IDH2 inhibition with AG-221 reversed aberrant methylation at many genes with a known role in hematopoietic proliferation and differentiation, including the master transcriptional factor RUNX1. We next assessed in vivo effects of the small-molecule IDH2-R140Q inhibitor in a mouse model of IDH2-mutant leukemia. We generated mice that simultaneously expressed a constitutive Flt3ITD knock-in allele and a conditional mutant IDH2R140Q knock-in allele. As reported recently using retroviral/transgenic models, Mx1-Cre IDH2R140QFlt3ITD developed fully penetrant, transplantable AML with expansion of c-Kit+ positive blasts in the peripheral blood, and widespread leukemic infiltration. AG-221 inhibited the serial replating capacity of IDH2R140QFlt3ITD expressing cells in vitro. We competitively transplanted IDH2R140QFlt3ITD AML cells and normal bone marrow cells into secondary recipients, and then assessed the effect of AG-221 therapy on leukemia in vivo and on disease burden. AG-221 (100mg/kg bid) treatment of mice engrafted with Mx1-Cre IDH2R140QFlt3ITD AML cells markedly reduced 2HG levels consistent with on target inhibition in vivo. AG-221 therapy induced differentiation of leukemic cells, with an increase in the CD11b+ population and a decrease in the c-Kit+ population in the peripheral blood at 2wks. We next assessed the impact of treatment with both AG-221 therapy with AC220, a potent, specific Flt3 inhibitor in late phase clinical trials. Combined IDH2R140Q and Flt3ITD inhibition resulted in a marked decrease in leukemic burden to vehicle-treated mice, with a significant reduction in leukemic cell chimerism in vivo in the setting of combined inhibition at 2 wks, (mean 45.2 fraction 88% veh, 73% AG-221, p<.01). These data demonstrate that AG-221 inhibits mutant IDH2-mediated 2-HG production in vivo and reverses the effects of mutant IDH2 on DNA methylation in mutant stem/progenitor cells. AG-221 induces differentiation and impairs self-renewal of IDH2-mutant leukemia cells, effects that are further enhanced by simultaneous inhibition of Flt3ITD. Clinical trials combining IDH2 inhibitors with other targeted AML therapies are warranted in order to increase therapeutic efficacy. Disclosures Intlekofer: Foundation Medicine, Inc: Consultancy. Thompson:Agios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Travins:Agios Pharmaceuticals: Employment, Stockholder Other. Straley:Agios: Employment, Equity Ownership. Gliser:Agios Pharmaceuticals: Employment, Stockholder Other. Yen:Agios: Employment, Equity Ownership. Levine:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 2, Randomized, Open-Label, 2-Arm Study Comparing 2 Intermittent Dosing Schedules of Duvelisib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) (TEMPO)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5251-5251
Author(s):  
Reem Karmali ◽  
Hagop Youssoufian ◽  
Kam Sprott ◽  
David T. Weaver ◽  
Narayana Narasimhan ◽  
...  
Keyword(s):  
Response Rate ◽  
Advisory Board ◽  
Small Lymphocytic Lymphoma ◽  
Open Label ◽  
Employment Equity ◽  
Drug Induced ◽  
Prior Therapy ◽  
History Of ◽  
Equity Ownership ◽  
Systemic Therapies

Background Duvelisib, an oral dual PI3K-δ and PI3K-γ inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior systemic therapies. In multiple phase 1-3 studies that included patients with iNHL, duvelisib was shown to be efficacious, with a favorable risk-benefit profile. This study will evaluate whether duvelisib efficacy at the approved 25 mg twice daily (BID) dose can be achieved and maintained with an acceptable or improved safety profile by the inclusion of prespecified 2-week drug holidays in patients with R/R iNHL. Study Design and Methods TEMPO is a randomized, open-label, multicenter, international, phase 2 study of duvelisib in adult patients with R/R iNHL in whom ≥ 1 line of prior therapy has failed. The primary objective is to evaluate the efficacy of duvelisib administered with prescribed drug holidays, with the primary endpoint of overall response rate (ORR) by the 2007 revised International Working Group criteria. Key secondary endpoints include ORR by the 2014 Lugano criteria, progression-free survival, overall survival, time to treatment failure, duration of response, lymph node response rate, time to the first response, adverse event profile, and determination of pharmacokinetics parameters. Exploratory objectives include assessment of quality of life and biomarkers of treatment response and toxicity. Key inclusion criteria include histologically confirmed FL grades 1 to 3a, marginal zone lymphoma (splenic, nodal, or extranodal) or small lymphocytic lymphoma, radiological evidence of disease progression and ≥ 1 bidimensionally measurable lesion ≥ 1.5 cm, adequate organ function, and Eastern Cooperative Oncology Group performance status ≤ 2. Key exclusion criteria include prior allogeneic hematopoietic stem cell transplant; previous treatment with a PI3K inhibitor; history of drug-induced colitis or drug-induced pneumonitis; ongoing treatment for systemic infection; central nervous system NHL; prolonged QT interval; history of tuberculosis treatment within the 2 past years; history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the past 6 months; history of or concurrent interstitial lung disease of any severity and/or severely impaired lung function; ongoing treatment with chronic immunosuppressants; and any unstable or severe uncontrolled medical condition. A total of 102 patients are planned to be enrolled. Patients will be randomized 1:1 to 2 arms and stratified by number of prior therapies (1 or > 1), bulky disease status (longest diameter of baseline lesion < 5 cm or ≥ 5 cm), and time since last recurrence (≥ 24 months or < 24 months). In arm 1, patients will receive duvelisib 25 mg BID for one 10-week (W) cycle followed by 25 mg BID on W3 and W4 of each subsequent 4-week cycle. In arm 2, patients will receive duvelisib 25 mg BID on W1, W2, W5, W6, W9, and W10 of one 10-week cycle and then on W3 and W4 of each subsequent 4-week cycle. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal. This study will test the null hypothesis that the ORR in each arm is ≤ 30% against the alternative that the ORR is ≥ 55%. The study has a 2-stage design. In stage 1, 15 patients will be enrolled in each arm, with response assessment after ≥ 3 cycles. If there are fewer than 6 partial or complete responses, consideration may be given to terminating the arm. Otherwise, in stage 2, 36 additional patients will be enrolled, for a total of 51 per arm. Enrollment is planned to be initiated in August 2019. Approximately 50 sites will be open for enrollment across the United States, Europe, and Asia. Disclosures Karmali: Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Sprott:SMOC Therapeutics: Employment, Equity Ownership; Verastem Oncology: Employment, Equity Ownership. Weaver:FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor; Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership. Narasimhan:Verastem: Employment, Equity Ownership. Lustgarten:Verastem: Employment. Patrick:Verastem Oncology: Employment. Zalutskaya:Verastem Inc: Employment, Equity Ownership. Gordon:Gilead: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy and R/R follicular lymphoma after at least two prior systemic therapies.

Candidate Gene Associations with Vaso-Occlusive Crisis in Children with Sickle Cell Anemia Enrolled in the Multinational DOVE Trial

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 962-962
Author(s):  
Carolyn C Hoppe ◽  
Joseph A Jakubowski ◽  
Wendra M Foster ◽  
Lori E Heath ◽  
Sreekumar Pillai ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Genetic Variants ◽  
Genetic Factors ◽  
Acute Chest Syndrome ◽  
Employment Equity ◽  
Platelet Counts ◽  
Study Population ◽  
Equity Ownership

Abstract Introduction: Sickle cell disease (SCD) is complex, with marked inter-individual variability in disease severity. The clinical heterogeneity of SCD is largely influenced by genetic factors, including several well-established modifiers of fetal hemoglobin (HbF) levels within the beta globin locus, BCL11A, and HBS1L-MYB genes. However, little is known about genetic factors that may influence variability in treatment response, particularly in clinical trials assessing potential therapeutic agents for SCD. The DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) study was a multinational, phase 3, randomized, double-blinded, placebo-controlled trial evaluating the efficacy and safety of the antiplatelet agent prasugrel for the reduction of vaso-occlusive crisis (VOC) in children with sickle cell anemia (NCT01794000). Although the primary endpoint of reduction of rate of VOC did not reach statistical significance in the DOVE trial in the ITT population, a treatment effect of prasugrel was suggested in certain subgroups. The objective of this study was to evaluate candidate genetic variants with SCD severity and to assess impact of these variants on response to prasugrel, as measured by the frequency of VOC (composite of painful crisis and acute chest syndrome events) during the study period of up to 24 months. Methods: De-identified dried blood spot samples were collected for genetic analyses as per informed consent and study protocol. Genomic DNA was extracted from a 3 mm Whatman FTA card punch using Qiagen QIAamp DNA kit. A total of 313 (92%) DOVE patients (Hb SS or Hb S/β0 thalassemia) were genotyped using the TaqMan assay. After quality control, 253 patients and 28 variants were considered for genetic evaluation. These variants have been reported to be associated with SCD and/or its related comorbidities. All variants were analyzed for VOC in the prasugrel and placebo groups separately and for treatment by variant interactions in the overall study population. Variants were also assessed in the overall study population for associations with a hemolytic score, derived from 5 biomarkers of hemolysis and baseline hematologic markers including leukocyte, neutrophil, and platelet counts, and red cell mean corpuscular volume. All analyses were conducted using additive multivariate regression framework as the main model and were adjusted for age, race, geographic region, and hydroxyurea (HU) use at baseline. In addition, genotypic, dominant, and recessive models were evaluated as supportive analyses. Results: Two variants, rs7482144, located in the 5'- HBG2 gene promoter (-158 Xmn1) on chr 11 and rs1427407, located in the BCL11A gene on chr 2, were associated with VOC and a treatment interaction effect of prasugrel. HBG2 rs7482144, was associated with a significant decrease in frequency of VOC in prasugrel-treated patients relative to placebo (adjusted p=0.0065). The BCL11A rs1427407 variant was associated with an increase in VOC in prasugrel-treated patients relative to placebo (adjusted p=0.0205). No genetic associations were found with baseline composite hemolytic score in the overall population. However, significant associations with KLF-1, HBG2, and HBE variants were observed with individual hematologic markers. The KLF-1 variant (rs112631212) was associated with lower leukocyte (p&lt;0.0001) and neutrophil (p=0.0002) counts in the subgroup of participants on HU; whereas the HBG2 (rs2070972; p=0.0116) and HBE (rs3834466 and rs7130110; p=0.0274 and p=0.0340 respectively) variants were associated with elevated platelet counts in the overall group. Conclusions: Given the study sample size, this study highlights the significance of HBG2 and BCL11A variants for the frequency of VOC in prasugrel-treated patients versus placebo. These variants have been reported in association with HbF/F-cells, an ameliorating factor for VOC that is only partly explained by endogenous levels of HbF. Our findings suggest that these variants may have contributed to the treatment-related effects of prasugrel on VOC outcomes in the DOVE trial. Identifying such genetic variants that are associated with differential response to treatment may help guide selection of patients for clinical trials based on predicted risk of VOC. Disclosures Hoppe: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jakubowski: Eli Lilly and Company: Employment, Equity Ownership, Other: Former employee and minor shareholder of Eli Lilly and Company. Foster: Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Heath: Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Pillai: Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Pallav: Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company.

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